Method Of Reducing Friction Between Syringe Components

ABSTRACT

A method of making a syringe assembly includes providing a first syringe component defining a first sliding surface that is substantially free of lubricant. The first sliding surface is contacted with water. The first sliding surface and the water in contact with the first sliding surface are heated at a temperature of at least 121° C. The first sliding surface is dried.

BACKGROUND

Syringes used for delivery of medicaments are principally constructed ofa barrel and a stopper. The stopper is slidably fitted within thesyringe barrel and may have a stopper rod affixed to it for actuation ofthe syringe and delivery of medicament. The stopper is generallyconstructed of an elastomer, with silicone oil applied. The silicone oilis applied to the stopper or barrel to reduce sliding friction betweenthe stopper and barrel and to improve the seal between them, which canbe helpful in ensuring a full dose is administered. Ease of sliding canbe important for proper operation of pens and so-called auto injectingsyringes. The oil helps prevent jamming of such devices, which canotherwise lead to trauma at the site of injection. The improved sealingprovided by silicone oil can also help ensure no foreign contaminants,such as bacteria, enter the syringe.

Recently there has developed a trend favoring pre-filled syringes whichfunction to both store and deliver medicaments. Such pre-filled syringesmay offer cost savings to the pharmaceutical industry and may improvesafety, convenience and efficacy of medicament delivery.Biopharmaceuticals are an important class of pharmaceuticals that mayincrease the use of pre-filled syringes and related devices (pens, autoinjectors and the like). Such biopharmaceuticals may include insulin,vaccines, antibodies, blood products, hormones, cytokines, and the like.As more pharmaceuticals and particularly biopharmaceuticals utilizedelivery in pre-filled syringes and similar devices, the challenges ofconventional syringe technology multiply.

Several aspects of traditional syringe construction present a challengefor their use as pre-filled syringes. The use of silicone oil is aconcern, because the oil may degrade the medicament and because a smallamount of silicone may be injected with it. The oil is of particularconcern with regard to biopharmaceuticals because it may causeaggregation of certain proteins.

Another issue that arises in pre-filled syringes is that the elastomerof the stopper may contain leachable and extractable contaminants. Thesemay also contaminate the medicament upon long term storage in syringes.Trace amounts of residual monomer or plasticizer or other impuritiesfrom the stopper can adversely affect the therapeutic function or canhave an adverse impact on the patient once injected.

Among the many other considerations affecting pre-filled syringe devicesand similar devices and their components are the need to be sterilized,stability with transport and storage for up to a few years, opticalclarity, the need to integrate into existing filling equipment(including the durability requirements for stopper cleaning andinsertion into the syringe barrel), leachables and extractables of allcomponents of the syringe, and the need to maintain sterility fromfilling through administering of the contents, and finally userpreferences and ergonomic considerations. For a variety ofconsiderations the pre-filled syringe market uses both glass and plasticbarrels.

Friction between stopper materials and syringe barrels can besignificant. As described above, lubricants such as silicone oil areproblematic. There is a need to reduce friction between stopper andbarrel without the use of oils or other lubricants that have undesirableeffects.

SUMMARY

Some aspects relate to a method of reducing sliding friction betweenglass and a stopper material. The method includes exposing glass to anaqueous solution at high temperature. For example, the glass isoptionally contacted with water for injection (WFI) water and placed inan autoclave set at a temperature at or above 120° C. Following theautoclave process, the glass is dried at about 90° C. Friction between astopper material and glass are thereby reduced significantly. In anotheraspect, the method may include rinsing the glass, for example with anorganic solvent.

Other aspects relate to a method of making a syringe assembly includingproviding a first syringe component defining a first sliding surfacethat is substantially free of lubricant. The first sliding surface iscontacted with water, the first sliding surface and the water in contactwith the first sliding surface are heated at a temperature of at least121° C., and the first sliding surface is dried.

Still other aspects relate to a component of a syringe assembly that isprepared for sliding engagement with a second, complementary componentof the syringe assembly by a process including contacting the firstsliding surface with WFI water. Saturated steam is applied to heat thefirst sliding surface and the WFI water in contact with the firstsliding surface and the first sliding surfaced is dried.

While multiple embodiments are disclosed, still other embodiments of thepresent invention will become apparent to those skilled in the art fromthe following detailed description, which shows and describesillustrative embodiments of the invention. Accordingly, the drawings anddetailed description are to be regarded as illustrative in nature andnot restrictive.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic view of a syringe assembly prepared according tosome embodiments.

FIG. 2 provides flow charts illustrating the methods of Examples 2 to 5.

FIG. 3 is a chart reflecting functional forces of Comparative Example 1and Example 2.

While the invention is amenable to various modifications and alternativeforms, specific embodiments have been shown by way of example in thedrawings and are described in detail below. The intention, however, isnot to limit the invention to the particular embodiments described. Onthe contrary, the invention is intended to cover all modifications,equivalents, and alternatives falling within the scope of the inventionas defined by the appended claims.

DETAILED DESCRIPTION

Various embodiments described herein address reducing sliding frictionbetween complementary sliding components in syringe assemblies, such asfriction reduction between a first, softer component and a second, morerigid component of a syringe assembly. For example, some embodimentsrelate to reducing friction between a syringe stopper and a barrel,between a syringe tip cap and a barrel, or between a syringe valve bodyand valve plug, or other complementary syringe components. In someembodiments, the first component (e.g., a stopper) includes anelastomeric material, such as butyl rubber, and the second component(e.g., a syringe barrel) includes a ceramic material, such asborosilicate glass. While various embodiments are described inassociation with syringe assembly applications, a variety ofapplications where reduced friction is sought are contemplated.

FIG. 1 is a schematic view of a syringe assembly 10, according to someembodiments. As shown, the syringe assembly 10 includes a syringe barrel12, a stopper 14 that forms a complementary fit with the syringe barrel12, a plunger rod 16, a tip cap or needle shield 18, and, in the case ofa pre-filled embodiment, a liquid 20, such as a medicament, fordispensing from the syringe assembly 10. As shown, the syringe barrel 12and the stopper 14 are first and second complementary syringe componentsthat are slidably engaged with one another, the stopper 14 forming aslidable seal within the syringe barrel 12. Although the syringe barrel12 and the stopper 14 are slidably engaged in a linear relationship, itshould be understood that other sliding relationships (e.g., rotationalsliding between a valve body and a valve plug) are contemplated.

As shown, the syringe barrel 12 defines a bore or inner surface 30, alsodescribed as a sliding surface. The syringe barrel 12 is formed of asuitable material, such as suitable ceramic, polymeric, and metalmaterials. In some embodiments, the syringe barrel 12 includes asubstantially rigid or hard material, such as a glass material. Althoughany of a variety of glass compositions are contemplated, according tothe examples that follow borosilicate glass has been shown to be aneffective material in association with friction-reduction methodsaccording to some embodiments.

As indicated in FIG. 1, the stopper 14 defines an outer surface 32 forslidably engaging the inner surface 30 of the syringe barrel 12. In someembodiments, the stopper 14 includes a softer material than the syringebarrel 12. For example, the stopper 14 is optionally constructed withone or more barrier films applied to an elastomeric core, where thebarrier film(s) define the outer surface 32 of the stopper 14. Theelastomeric core can be formed of a variety of elastomeric materials,including: Butyl Rubber, Silicon, materials sold under the trade name“VITON”, and the like. The barrier film or films optionally includeexpanded fluoropolymer films and, such as expandedpolytetrafluoroethylene films. Barrier films based on expanded PTFE helpprovide for thin and strong barrier layers to leachables andextractables. Some examples of suitable stopper designs utilizingexpanded PTFE and elastomeric materials are described in U.S.application Ser. No. 12/915,850, “SYRINGE STOPPER” by Ashmead et al.,filed Oct. 29, 2010, the entire contents of which are incorporatedherein by reference for all purposes.

In some embodiment methods of reducing friction between the stopper 14and the syringe barrel 12 of the syringe assembly 10, the syringe barrel12 is filled with WFI water and sealed to prevent leakage. A cap, asecond stopper, or other sealing member (not shown) different than thestopper 14 is optionally utilized to seal the WFI water within thesyringe barrel 12. In other embodiments, the assembly 10, including thestopper 14 is filled with WFI water. The WFI water filled syringe barrel12 is exposed to a source of heat, such as saturated steam. For example,the WFI water filled syringe barrel 12 may be placed in an autoclavewith the temperature set at 121° C. or above. The saturated steam willheat the WFI water and the syringe barrel 12. The WFI water is removedand the syringe barrel 12 is dried. Following drying, the syringe barrel12 is ready for use. Syringe assemblies with syringe barrels thusprepared display lower frictional forces between the syringe barrel 12and the stopper 14.

In some embodiments, the syringe barrel 12 is rinsed with an organicsolvent after the syringe barrel 12 and associated WFI water have beenheated with steam. For example, a Hexane solvent may be used to rinsethe syringe barrel 12. After the rinsing step, the syringe barrel 12 isdried. Drying may be conducted at room temperature (RT) or at elevatedtemperatures (e.g., at about 90° C. or greater, from about 70° C. toabout 110° C., other at other temperature(s) as desired). The followingexamples are illustrative of methods of preparing a syringe assembly 10with reduced friction according to some embodiments. While variousmethods of reducing friction between the syringe barrel 12 and thestopper 14 have been described, it should be understood that in otherimplementations similar methodology is applied to reduce frictionbetween alternative or additional components of the syringe assembly 10,such as between the syringe barrel 12 and the tip cap 18, for example.

EXAMPLES

A syringe stopper was constructed in the following manner: A layer ofFEP about 0.5 mils in thickness (FEP 100, DuPont) was laminated to alayer of densified expanded PTFE film [thickness: 1 mil; tensilestrength: 13.85 ksi (longitudinal), 13.9 ksi (transverse); modulus: 19.8ksi (longitudinal), 20.7 ksi (transverse); strain to break: 425%(longitudinal), 425% (transverse)]. The two layers were stacked on topof each other in a pin frame and heating to 380° C. in an oven for 15minutes. A layer of porous expanded PTFE [thickness: 27.5 micrometers,matrix tensile strength: 66.8 MPa (longitudinal), 75.8 MPa (transverse),strain to break: 131% (longitudinal), 91% (transverse), bubble point:22.6 psi] was placed on the densified ePTFE-FEP laminate such that theporous expanded PTFE layer faced the FEP layer in the laminate. Thesethree layers were placed between two smooth metal plates, the plateswere clamped to a clamping pressure of about 1 psi. The plates were thenplaced in an oven at 305° C. for 15 minutes. The resulting three layercomposite material (densified ePTFE—FEP—porous ePTFE) was then cooled toabout 40° C.

This composite material was then thermoformed using heat and vacuum tocreate a pre-form. The pre-form was constructed by heating the compositeto a sufficiently high temperature and then drawing the composite over amale plug using differential pressure. The composite material was loadedinto the thermoforming apparatus such that the densified ePTFE layerfaced the plug. The composite was heated using a hot air gun (SteinelHG2310) with air exit temperature of 380° C. by placing the gun about 5mm away from the surface of the composite. After 5 seconds, the film wassubjected to a vacuum of −85 kPa. The composite was continued to beheated for another 15 seconds and cooled to about 40° C. under vacuum.

The resulting pre-form sample was then inverted and then placed into arubber molding cavity charged with 3.5 grams of elastomer (50 Durometerhalobutyl rubber), and the stopper was formed by compression molding.The mold was built to geometry specified for 1 mL “long” plunger per theISO standard ISO11040-5:2001(E), with an additional 2% shrinkage factorincorporated.

The cavity was loaded in a press with both platens preheated to 120° C.The platens were closed to 55,500 lbs (about 8700 psi total internalpressure). The platens were then heated at 180° C. for 5 minutes andthen cooled under pressure to 40° C. The pressure was released and thestopper was ejected. The resulting stopper was washed using a detergentand triple rinsed with de-ionized water. Stopper samples were then cutfrom the release sheet using a razor blade. They were subjected to two30 minute cycles in an autoclave at 121° C.

As constructed, the stoppers were used as in the following examples,which reflect the improved sliding friction of the present inventionwhen compared to that of the comparative example. A new stopper was usedin each of the examples. FIG. 2 provides flow charts illustrating themethods of Examples 2 to 5.

Comparative Example 1 “As delivered”

A borosilicate glass syringe (1 mL Long Schott form a 3 s with a stakedneedle) was obtained. The syringe was obtained without silicone oilapplied. A stopper constructed as described above was inserted into thebarrel of the syringe and the Dynamic force was measured. Results arereported in Table 1.

Example 2

A syringe according to the inventive method was constructed in thefollowing manner: A glass syringe free of silicone oil identical to thatused in Example 1 was filled with WFI grade water and placed in anautoclave (121° C. for 1 hr), the glass syringe was then dried at 90° C.for 60 minutes and allowed to cool overnight. The stopper was theninserted into the syringe and the dynamic force was measured to be 4.7N.Results are reported in Table 1.

Example 3

A glass syringe free of silicone oil identical to that of Example 1 wasfilled with WFI grade water and placed in an autoclave (121° C. for 1hr), the glass syringe was then removed from the autoclave, rinsed withhexane and dried at room temperature overnight in a laboratory hood.Another stopper was then inserted into this syringe and the dynamicforce was measured to be 1.1N. Results are reported in Table 1.

Example 4

A glass syringe free of silicone oil identical to that of ComparativeExample 1 was filled with WFI grade water and placed in an autoclave(121° C. for 1 hr), the glass syringe was then removed from theautoclave and dried at room temperature overnight in a laboratory hood.The stopper was then inserted into this syringe and the dynamic forcewas measured to be 5.9N. Results are reported in Table 1.

Example 5

A glass syringe free of silicone oil identical to that of ComparativeExample 1 was filled with WFI grade water and placed in an autoclave(121° C. for 1 hr), the glass syringe was then removed from theautoclave and then dried at 90° C. for 60 minutes. The syringe was thenrinsed with hexane and allowed to dry overnight in a laboratory hood.The stopper was then inserted into this syringe and the dynamic forcewas measured to be 4.4 N. Results are reported in Table 1.

Example 6

The syringe of Example 2 was tested per the dye ingress test in USP<381> to evaluate the seal between the inside of the syringe barrel andthe stopper from Example 1. No significant dye ingress was observed.

TABLE 1 Static Dynamic Force (N) Force (N) Comparative 10.1 8.5 Example1 Example 2 7.0 4.7 Example 3 7.3 1.1 Example 4 8.5 5.9 Example 5 6.44.4

As shown in Table 1, subjecting the glass syringe to the treatmentsdescribed in Examples 2 through 5 lower the dynamic and static force ofthe stopper.

Test Methods:

Static and Dynamic Force Test

The test was performed as specified by I.S. EN ISO 7886-1:1998 Annex G,with the following exceptions: i) Syringe is mounted so that nozzle ispointing down, ii) No liquid was expelled; only air was expelled, andiii) Forces resulting from travel from the total graduated capacityposition to 20 mm from that point were recorded. Static force is definedas the value at the first inflection point in the force versusdisplacement graph. Dynamic force is the value after the inflectionpoint during travel.

Tensile, Modulus, Strain to Break

Materials were evaluated for tensile strength, modulus and strain tobreak according to ATM D882-10 using 0.25 inch by 3 inch samples and across head rate of 20 inches/min and one inch gauge length.

Various modifications and additions can be made to the exemplaryembodiments discussed without departing from the scope of the presentinvention. For example, while the embodiments described above refer toparticular features, the scope of this invention also includesembodiments having different combinations of features and embodimentsthat do not include all of the described features. Accordingly, thescope of the present invention is intended to embrace all suchalternatives, modifications, and variations as fall within the scope ofthe claims, together with all equivalents thereof.

What is claimed is:
 1. A method of treating a syringe assemblycomprising: providing a glass barrel having a glass sliding surface forsliding engagement with a complementary component of a syringe assembly;applying saturated steam to heat the glass sliding surface; maintainingthe saturated steam at a temperature at or above 120° C. for at least 60minutes; and drying the glass sliding surface, wherein a friction forceof the glass sliding surface is reduced.
 2. The method of claim 1,wherein the glass sliding surface is an interior surface of the glassbarrel.
 3. The method of claim 2, wherein the glass sliding surface issubstantially free of silicone oil.
 4. The method of claim 1, whereinthe method is achieved within a sterilization cycle.
 5. The method ofclaim 1, wherein the glass sliding surface is dried at about 90° C. orgreater.
 6. The method of claim 1, comprising rinsing the glass slidingsurface with an organic solvent.
 7. The method of claim 1, wherein thecomplementary component is a syringe stopper or a syringe tip cap. 8.The method of claim 1, wherein the glass barrel contains therein waterfor injection.
 9. The method of claim 7, comprising removing the waterfor injection prior to the drying.
 10. The method of claim 1, comprisingplacing the barrel into an autoclave prior to the application ofsaturated steam.